Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma

Talal El Zarif; Karl Semaan; Marc Eid; Ji Heui Seo; Simon Garinet; Matthew P. Davidsohn; Pranshu Sahgal; Brad Fortunato; John Canniff; Amin H. Nassar; Sarah Abou Alaiwi; Ziad Bakouny; Gitanjali Lakshminarayanan; Hunter Savignano; Kevin Lyons; Sayed Matar; Atef Ali; Eddy Saad; Renee Maria Saliby; Paulo Cordeiro; Ziwei Zhang; Nourhan El Ahmar; Yasmin Nabil Laimon; Chris Labaki; Valisha Shah; Dory Freeman; Jillian O'Toole; Gwo Shu Mary Lee; Justin Hwang; Mark Pomerantz; Sabina Signoretti; Eliezer M. Van Allen; Wanling Xie; Jacob E. Berchuck; Srinivas R. Viswanathan; David A. Braun; Toni K. Choueiri; Matthew L. Freedman; Sylvan C. Baca

doi:10.1016/j.celrep.2024.114350

Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma

Talal El Zarif, Karl Semaan, Marc Eid, Ji Heui Seo, Simon Garinet, Matthew P. Davidsohn, Pranshu Sahgal, Brad Fortunato, John Canniff, Amin H. Nassar, Sarah Abou Alaiwi, Ziad Bakouny, Gitanjali Lakshminarayanan, Hunter Savignano, Kevin Lyons, Sayed Matar, Atef Ali, Eddy Saad, Renee Maria Saliby, Paulo CordeiroZiwei Zhang, Nourhan El Ahmar, Yasmin Nabil Laimon, Chris Labaki, Valisha Shah, Dory Freeman, Jillian O'Toole, Gwo Shu Mary Lee, Justin Hwang, Mark Pomerantz, Sabina Signoretti, Eliezer M. Van Allen, Wanling Xie, Jacob E. Berchuck, Srinivas R. Viswanathan, David A. Braun, Toni K. Choueiri, Matthew L. Freedman, Sylvan C. Baca

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

Original language	English (US)
Article number	114350
Journal	Cell reports
Volume	43
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2024.114350
State	Published - Jun 25 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Keywords

CP: Cancer
CP: Genomics
FOSL1
epigenomics
histone modifications
immune checkpoint inhibitors
immunotherapy
kidney cancer
liquid biopsy
renal cell carcinoma
sarcomatoid
transcription factors

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1016/j.celrep.2024.114350

Find It

Find It at U of M Libraries

Cite this

El Zarif, T., Semaan, K., Eid, M., Seo, J. H., Garinet, S., Davidsohn, M. P., Sahgal, P., Fortunato, B., Canniff, J., Nassar, A. H., Abou Alaiwi, S., Bakouny, Z., Lakshminarayanan, G., Savignano, H., Lyons, K., Matar, S., Ali, A., Saad, E., Saliby, R. M., ... Baca, S. C. (2024). Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma. Cell reports, 43(6), Article 114350. https://doi.org/10.1016/j.celrep.2024.114350

El Zarif, T, Semaan, K, Eid, M, Seo, JH, Garinet, S, Davidsohn, MP, Sahgal, P, Fortunato, B, Canniff, J, Nassar, AH, Abou Alaiwi, S, Bakouny, Z, Lakshminarayanan, G, Savignano, H, Lyons, K, Matar, S, Ali, A, Saad, E, Saliby, RM, Cordeiro, P, Zhang, Z, El Ahmar, N, Laimon, YN, Labaki, C, Shah, V, Freeman, D, O'Toole, J, Lee, GSM, Hwang, J, Pomerantz, M, Signoretti, S, Van Allen, EM, Xie, W, Berchuck, JE, Viswanathan, SR, Braun, DA, Choueiri, TK, Freedman, ML & Baca, SC 2024, 'Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma', Cell reports, vol. 43, no. 6, 114350. https://doi.org/10.1016/j.celrep.2024.114350

@article{f907b1f5832d4271acea487becc6d242,

title = "Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma",

abstract = "Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.",

keywords = "CP: Cancer, CP: Genomics, FOSL1, epigenomics, histone modifications, immune checkpoint inhibitors, immunotherapy, kidney cancer, liquid biopsy, renal cell carcinoma, sarcomatoid, transcription factors",

author = "{El Zarif}, Talal and Karl Semaan and Marc Eid and Seo, {Ji Heui} and Simon Garinet and Davidsohn, {Matthew P.} and Pranshu Sahgal and Brad Fortunato and John Canniff and Nassar, {Amin H.} and {Abou Alaiwi}, Sarah and Ziad Bakouny and Gitanjali Lakshminarayanan and Hunter Savignano and Kevin Lyons and Sayed Matar and Atef Ali and Eddy Saad and Saliby, {Renee Maria} and Paulo Cordeiro and Ziwei Zhang and {El Ahmar}, Nourhan and Laimon, {Yasmin Nabil} and Chris Labaki and Valisha Shah and Dory Freeman and Jillian O'Toole and Lee, {Gwo Shu Mary} and Justin Hwang and Mark Pomerantz and Sabina Signoretti and {Van Allen}, {Eliezer M.} and Wanling Xie and Berchuck, {Jacob E.} and Viswanathan, {Srinivas R.} and Braun, {David A.} and Choueiri, {Toni K.} and Freedman, {Matthew L.} and Baca, {Sylvan C.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = jun,

day = "25",

doi = "10.1016/j.celrep.2024.114350",

language = "English (US)",

volume = "43",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma

AU - El Zarif, Talal

AU - Semaan, Karl

AU - Eid, Marc

AU - Seo, Ji Heui

AU - Garinet, Simon

AU - Davidsohn, Matthew P.

AU - Sahgal, Pranshu

AU - Fortunato, Brad

AU - Canniff, John

AU - Nassar, Amin H.

AU - Abou Alaiwi, Sarah

AU - Bakouny, Ziad

AU - Lakshminarayanan, Gitanjali

AU - Savignano, Hunter

AU - Lyons, Kevin

AU - Matar, Sayed

AU - Ali, Atef

AU - Saad, Eddy

AU - Saliby, Renee Maria

AU - Cordeiro, Paulo

AU - Zhang, Ziwei

AU - El Ahmar, Nourhan

AU - Laimon, Yasmin Nabil

AU - Labaki, Chris

AU - Shah, Valisha

AU - Freeman, Dory

AU - O'Toole, Jillian

AU - Lee, Gwo Shu Mary

AU - Hwang, Justin

AU - Pomerantz, Mark

AU - Signoretti, Sabina

AU - Van Allen, Eliezer M.

AU - Xie, Wanling

AU - Berchuck, Jacob E.

AU - Viswanathan, Srinivas R.

AU - Braun, David A.

AU - Choueiri, Toni K.

AU - Freedman, Matthew L.

AU - Baca, Sylvan C.

PY - 2024/6/25

Y1 - 2024/6/25

N2 - Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

AB - Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

KW - CP: Cancer

KW - CP: Genomics

KW - FOSL1

KW - epigenomics

KW - histone modifications

KW - immune checkpoint inhibitors

KW - immunotherapy

KW - kidney cancer

KW - liquid biopsy

KW - renal cell carcinoma

KW - sarcomatoid

KW - transcription factors

UR - http://www.scopus.com/inward/record.url?scp=85195591888&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85195591888&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2024.114350

DO - 10.1016/j.celrep.2024.114350

M3 - Article

C2 - 38870013

AN - SCOPUS:85195591888

SN - 2211-1247

VL - 43

JO - Cell reports

JF - Cell reports

IS - 6

M1 - 114350

ER -

Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this